Volunteers needed to test new smallpox vaccine

February 16, 2005

Researchers at the Stanford University School of Medicine are conducting a clinical trial that will test whether a new type of smallpox vaccine can produce immunity in adults as well as — or better than — the vaccine currently available in the United States. They also hope to determine whether the new vaccine is safer than the old. The results of this study, for which volunteers are now being sought, may provide another option to prevent people from coming down with the disease in the event of a smallpox outbreak.

Smallpox is caused by the variola virus that emerged in human populations thousands of years ago. The World Health Organization’s global smallpox eradication campaign effectively eliminated the virus from the human population several decades ago, with the last natural case occurring in Somalia in 1977.

“However, it is not true that smallpox is totally gone,” said Jose Montoya, MD, associate professor of medicine (infectious diseases and geographic medicine) and the study’s leader. “Stockpiles still exist and the threat of bioterrorism, while always present, is heightened after Sept. 11.”

Adding to the seriousness of the threat is that the smallpox eradication campaign actually created a population once again susceptible to infection. In the United States, routine smallpox vaccination was discontinued in 1972. The U.S. military recognized this weakness, and in the last few years it has ramped up a vaccination program for its personnel. Still, if an attack were to occur, the public would need to be protected too, Montoya said.

Smallpox virus is considered one of the most dangerous potential biological weapons because it kills about 30 percent of those infected and is easily transmitted from person to person, a factor that is compounded by the scarcity of people who carry full immunity against it. There is no cure for the disease, but a vaccination given up to five days after exposure has been shown to be effective.

Montoya’s group is comparing an investigational vaccine-LC16m8, developed by California-based VaxGen, Inc. in partnership with the Chemo-Sero Therapeutic Research Institute (Kaketsuken) of Japan-with Dryvax, the only smallpox vaccine currently licensed for use in the United States.

Unlike Dryvax, which is made from live virus, LC16m8 has been attenuated, or modified. This means that it may be safer than conventional live-virus vaccines. Attenuated vaccines can initiate an immune response without causing serious adverse side effects. What’s more, there are a number of people who cannot use Dryvax-it can’t be given to people with certain skin conditions, such as eczema, or to those whose immune systems have been severely weakened because of AIDS or chemotherapy. Additionally, Dryvax can occasionally cause heart muscle inflammation.

Although LC16m8 is already licensed in Japan and has been used successfully to vaccinate more than 50,000 children there, U.S. regulations require that it be tested in Americans before it can be approved here.

Stanford is one of four centers looking to see if the investigational vaccine is safer than the one currently in use. In addition, the groups will see if the antibody and cellular immune responses are the same or better, said Montoya. He added that these vaccines have not been compared head-to-head before this study.

The clinical trial is currently enrolling a total of 150 volunteers (45 at Stanford) between the ages of 18 and 33 for this yearlong study. The participants will be randomly assigned to receive LC16m8 or Dryvax. Neither the participants nor the researchers will know who receives which vaccine. VaxGen and the National Institutes of Health fund the work.

No people will be exposed to smallpox as a part of LC16m8 clinical studies. Montoya explained that while it would be valuable to know whether the vaccine is effective against smallpox, for obvious reasons the tests of effectiveness must be done in animals. A study published in May 2004 demonstrated that LC16m8 provided complete protection against poxvirus-an animal virus similar to smallpox-infection in both rabbits and mice. Future studies will be required to confirm the vaccine candidate’s efficacy.

Of the participating sites, Stanford will be the only one that will profile the gene responses of patients in response to the vaccination. Using DNA microarrays, David Relman, MD, associate professor of medicine and of microbiology and immunology, and graduate student Kate Rubins will look at specific immune cells in the blood. They will compare samples from five patients receiving the standard vaccine to five receiving the investigational one. In this way, said Montoya, they can directly visualize any genes that are activated differently between the two vaccines. All participants will be carefully monitored immediately following vaccination and will return to the medical center for at least eight clinic visits, including an echocardiogram to look for heart abnormalities.

Stanford will begin screening potential participants in February. Interested individuals should call Frederic Janson at (650) 498-7284 for more information.